transforming-growth-factor-beta and Cholelithiasis

Cholangiocarcinoma (CCA) is one of the most frequent malignant epithelial liver tumors after hepatocellular carcinoma (HCC). Its incidence seems to be increasing worldwide, although risk factors are heterogeneous and differ globally. Although diagnostic and therapeutic medicine have advanced in several countries, tackling this tumor remains a challenge. The causes of CCA's increasing incidence are likely a differential increment of some factors according to the geographical area, which will be considered in this review. Environment-linked risk factors may play a critical role in the carcinogenesis. Liver flukes may play a major role in East Asia, while exposure to chemical compounds, such as naphthenic acids, has been postulated as a source of the rate increase in Western countries. Carcinogenesis is variable and confounding factors also need to be taken into account. Carcinogenesis depends on a sequential process and most probably involves both cholestasis and chronic inflammation as promoting steps after induction. The release and interaction of interleukin-6 (IL-6), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), and platelet-derived growth factor (PDGF) are at the basis of the proliferation of biliary epithelial cells or cholangiocytes. Additional steps for the final development of CCA may also involve an increase of the mutation rate of tumor suppressor genes, such as TP53, and the evasion of apoptosis.

Topics: Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biliary Tract; Cell Transformation, Neoplastic; Cholangiocarcinoma; Cholelithiasis; Fasciola hepatica; Hepatitis C; Humans; Incidence; Interleukin-6; Liver; Petroleum; Platelet-Derived Growth Factor; Risk Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The expression of several growth factors and K-ras gene mutation in bile were studied to better understand the pathogenesis and improve early diagnosis of bile duct cancers. Bile samples were collected from 12 cholangiocarcinomas (CLC), 10 ampullary cancers (APC), 3 gallbladder cancers (GBC), 7 pancreatic cancers (PNC), 9 biliary tract infection (BTI), 8 biliary stone disease (ST), and 5 normal controls (NC). The highest mean value of TGF-beta in bile was in patients with BTI; the mean levels of bFGF and PDGF were highest in CLC, and patients with APC and CLC had higher expression of HER2/Neu than other groups. In bile, a K-ras gene codon 12 mutation was found in 5 of 6 (83%) cases of CLC by the PCR-RFLP method. The results suggest overexpression of bFGF, PDGF, and HER2/Neu and the presence of K-ras mutation are important for carcinogenesis of bile duct cancers, and detection of the above abnormalities in bile is helpful for early diagnosis.

Topics: Ampulla of Vater; Bile; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biliary Tract Diseases; Biliary Tract Neoplasms; Biomarkers; Biomarkers, Tumor; Cholangiocarcinoma; Cholelithiasis; Common Bile Duct Neoplasms; Enzyme-Linked Immunosorbent Assay; Gallbladder Neoplasms; Humans; Infections; Pancreatic Neoplasms; Platelet-Derived Growth Factor; Polymerase Chain Reaction; ras Proteins; Receptor, ErbB-2; Transforming Growth Factor beta

Some monocytic cytokines are important immune regulators. We have investigated cytokine production by monocytes and the blood levels of IL-1 beta, IL-6, TNF alpha, and TGF beta, in patients with obstructive jaundice. The supernatant from LPS stimulated monocytes from jaundiced patients released significantly increased quantities of TNF alpha by both bioassay and radioimmunoassay (RIA) (12.4 +/- 2.5 fmol/mL and 32.6 +/- 8.3 fmol/mL, respectively, for jaundice, compared with 1.6 +/- 0.3 fmol/mL and 2.4 +/- 0.5 fmol/mL respectively for controls, and also of IL-6 (54.8 +/- 5.0 fmol/mL in jaundice compared with 35.6 +/- 5.0 fmol/mL for controls). The production of IL-1 beta and TGF beta by stimulated monocytes was unchanged. Jaundiced patients had significantly higher plasma TGF beta, but TNF alpha and IL-1 beta were below the limits of detection. The highest monocyte TNF alpha and IL-6 levels were seen in malignant disease patients, especially those with a poor immediate prognosis. We conclude that the production of some cytokines by monocytes is up-regulated in patients with obstructive jaundice.

Topics: Bile Duct Diseases; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Case-Control Studies; Cholangiocarcinoma; Cholelithiasis; Cholestasis; Cytokines; Female; Humans; Interleukin-1; Interleukin-6; Male; Middle Aged; Monocytes; Pancreatic Neoplasms; Prognosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

The gallbladder muscular layers of the patients with cholecystolithiasis were examined to evaluate the relationship between the gallbladder contractility and fibrosis in the muscular layers. Gallbladder contractility decreased as the fibrosis of muscular layers became severe. The density of the antimacrophage (M phi) antibody positive cells in the muscular layers was apparently greater in the remarkable fibrosis group than in the unremarkable fibrosis group, and the density of the anti-TGF-beta antibody positive cells in the remarkable fibrosis group was significantly greater than in the unremarkable fibrosis group. Smooth muscle cells in the muscular layers had changed morphologically from a contractile type to a synthetic type, and fibroblasts were frequently observed in the muscular layers of the remarkable fibrosis group. Immunohistochemically, type III collagen was detected in the rough endoplasmic reticulum not only of fibroblasts but also of synthetic type-smooth muscle cells. These results suggest that the fibrosis in the muscular layers is one of the factors responsible for reduced gallbladder contractility in patients with cholecystolithiasis, and the increase of M phi, fibroblasts and synthetic type-smooth muscle cells is involved in such a fibrotic change of the gallbladder muscular layers.

Topics: Cholelithiasis; Collagen; Fibrosis; Gallbladder; Humans; Immunohistochemistry; Muscle Contraction; Muscle, Smooth; Transforming Growth Factor beta